Over the last two decades, the rate of increase in adenocarcinoma of the esophagus has exceeded that of any other carcinoma in the United States. Specialized columnar metaplasia of the intestinal type at the gastroesophageal junction or Barrett's esophagus, is recognized as a major risk factor for the development of dysplasia and adenocarcinoma of the esophagus. Injury of the esophageal squamous epithelium by acid reflux from the stomach or by H. pylori infection is thought to lead to the replacement of the squamous epithelium by glandular epithelium, followed by the appearance of intestinal-type goblet cells, which are not normally found in the stomach or esophagus. The specific cellular events leading to Barrett's esophagus, including the origin of the metaplastic cells (squamous vs. glandular) and the time course for the conversion to an intestinal phenotype are not well characterized. The overall goals of this proposal are to develop and utilize an inducible transgenic mouse model of Barrett's esophagus to study the pathogenesis of this disorder. We isolated the keratin 15 promoter that drives expression of transgenes to the squamous epithelium of the esophagus and forestomach in mice. By expressing the K15/HSV-1 thymidine kinase suicide gene using this promoter, we discovered that intestinal metaplasia that closely mimics Barret's esophagus develops at the squamocolumnar junction after administration of ganciclovir. In this proposal, we plan to: 1. further develop and molecularly validate this transgenic mouse model for Barrett's esophagus, 2. study changes in gene expression in the tissue at the squamocolumnar junction as it develops intestinal metaplasia following injury.